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4′-C-substituted-2-haloadenosine derivative

a derivative and c-substitute technology, applied in the field of 4′csubstituted2haloadenosine derivatives, can solve the problems of not being able to achieve the effects of d4t, halogen atoms remain unknown, and the selectivity index cannot be improved, so as to achieve enhanced anti-hiv activity, anti-hiv activity is higher, and the effect of antiviral activity

Active Publication Date: 2008-03-04
YAMASA SHOYU CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a new compound, 2′-deoxy-4′-C-ethynyl-2-fluoroadenosine, which has resistance to inactivation by adenosine deaminase and potent antiviral activity against a multi-drug-resistant virus strain exhibiting resistance to various anti-HIV drugs such as AZT, ddI, ddC, d4T, and 3TC. The compound also exhibits enhanced anti-HIV activity and lowered cytotoxicity. The invention also provides a variety of 4′-C-substituted-2-haloadenosine derivatives, which have similar properties to the new compound. The technical effect of the invention is the development of new compounds with excellent anti-HIV activity and low cytotoxicity, which can be used for producing pharmaceuticals, particularly drugs for treating AIDS.

Problems solved by technology

However, whether or not selectivity index can be improved through introduction of a halogen atom has remained unknown.
However, effects similar to those of d4T are not expected to be obtained in an adenosine derivative, which is a purine nucleoside, whose basic skeleton differs considerably from that of d4T, and therefore, this literature does not provide useful information for the present inventors' purposes.

Method used

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  • 4′-C-substituted-2-haloadenosine derivative
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  • 4′-C-substituted-2-haloadenosine derivative

Examples

Experimental program
Comparison scheme
Effect test

synthesis example 1

Synthesis of 2′-deoxy-4′-C-ethynyl-2-fluoroadenosine (Compound 4)

(1) Synthesis of 9-(3,5-di-O-acetyl-2-deoxy-4-C-ethynyl-β-D-ribo-pentofuranosyl)-2,6-diaminopurine (Compound 2)

[0126]

[0127]Compound 1 (0.33 g, 1.14 mmol) was suspended in acetonitrile (10.0 ml), and acetic anhydride (0.23 ml, 2.43 mmol), triethylamine (0.67 g, 4.81 mmol), and a small amount of 4-dimethylaminopyridine were added to the resultant suspension, followed by stirring at room temperature overnight.

[0128]The thus-precipitated crystals were filtered and dried, to thereby yield compound 2 (0.40 g, 1.07 mmol, 93.9%).

[0129]1H-NMR(DMSO-d6)δ7.94(1H, s, H-8), 6.76(2H, bs, NH2), 6.27(1H, t, H-1′, J=7.00), 5.84(2H, bs, NH2), 5.60(1H, dd, H-3′, J=4.00, 6.80), 4.46(1H, d, H-5′a, J=11.5), 4.21(1H, d, H-5′b, J=11.5), 3.74(1H, s, ethynyl) 3.12(1H, m, H-2′a), 2.52(1H, m, H-2′b), 2.12, 2.03(each 3H, s, acetyl)

(2) Synthesis of 3′, 5′-di-O-acetyl-2′-deoxy-4′-C-ethynyl-2-fluoroadenosine (Compound 3)

[0130]

[0131]Compound 2 (450 mg,...

synthesis example 2

Synthesis of 4′-C-cyano-2′-deoxy-2-fluoroadenosine (Compound 8)

(1) Synthesis of 9-(3,5-di-O-acetyl-4-C-cyano-2-deoxy-β-D-ribo-pentofuranosyl)-2,6-diaminopurine (Compound 6)

[0136]

[0137]Compound 5 (122 mg, 0.418 mmol) was suspended in acetonitrile (5.00 ml), and acetic anhydride (118 μl, 1.25 mmol), triethylamine (352 μl, 2.51 mmol), and a small amount of 4-dimethylaminopyridine were added to the resultant suspension, followed by stirring at room temperature overnight. The thus-precipitated crystals were filtered and dried, to thereby yield compound 6 (128 mg, 0.341 mmol, 81.6%).

[0138]1H-NMR(CDCl3) δ7.54(1H, s, H-8), 6.31(1H, t, H-1′, J=7.00), 6.06(1H, dd, H-3′, J=5.00, 6.50), 5.31(2H, bs, NH2), 4.95(1H, d, H-5′a, J=11.5), 4.80(2H, bs, NH2), 4.37(1H, d, H-5′b, J=12.0), 3.43(1H, m, H-2′a), 2.63(1H, m, H-2′b), 2.23, 2.12(each 3H, s, acetyl).

(2) Synthesis of 3′, 5′-di-O-acetyl-4′-C-cyano-2′-deoxy-2-fluoroadenosine (Compound 7)

[0139]

[0140]Compound 6 (118 mg, 0.314 mmol) was dissolved in 7...

synthesis example 3

Synthesis of 2-chloro-2′-deoxy-4′-C-ethynyladenosine (Compound 9)

[0145]

[0146]Benzyltriethylammonium nitrite (1.04 g, 4.36 mmol) was dissolved in dichloromethane (24.0 ml), and acetyl chloride (0.40 ml, 5.63 mmol) was added to the resultant solution, followed by stirring at 0° C. for 30 minutes. To the resultant solution, a solution of compound 2 (340 mg, 0.91 mmol) in dichloromethane (6.00 ml) was added, and the resultant mixture was stirred at 0° C. for three hours. The resultant reaction mixture was diluted with chloroform, and subsequently the resultant organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the resultant residue, 28% aqueous ammonia (10.0 ml) and methanol (15.0 ml) were added, and the resultant mixture was stirred at room temperature overnight. Thereafter, the resultant reaction mixture was concentrated under reduced pressure, and the resultant residue was purified by means of silica gel column chr...

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Abstract

The present invention provides a 4′-C-substituted-2-haloadenosine derivative represented by the following formula [I], [II], or [III]:(wherein X represents a halogen atom, R1 represents an ethynyl group or a cyano group, and R2 represents hydrogen, a phosphate residue, or a phosphate derivative residue). The present invention also provides a pharmaceutical composition containing the derivative and a pharmaceutically acceptable carrier therefor. Such derivative is useful as medicine for the treatment of Acquired Immune Deficiency Syndrome (AIDS).

Description

BACKGROUND OF THE INVENTION[0001]1. Field of the Invention[0002]The present invention relates to 4′-C-substituted-2-haloadenosine derivatives and use thereof as a medicine, in particular a medicine which is useful for the treatment of acquired immunodeficiency syndrome (AIDS).[0003]2. Background Art[0004]The clinical setting for AIDS has been dramatically changed by a multi-drug combination therapy, which is sometimes called highly active antiretroviral therapy, or HAART. In HAART, nucleoside reverse transcriptase inhibitors (NRTIs) such as zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), and lamivudine (3TC), and protease inhibitors (PIs) are employed in combination.[0005]Although HAART has drastically decreased the number of deaths caused by AIDS, there has emerged a multi-drug resistant HIV-1 (human immunodeficiency virus-1) mutant exhibiting cross-resistance to various drugs. For example, in the early 1990s patients infected with an HIV exhibiting resistan...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07H19/173C07H19/20A61K31/70C07H19/16
CPCC07H19/16A61P31/18A61P37/00A61P43/00
Inventor KOHGO, SATORUOHRUI, HIROSHIKODAMA, EIICHIMATSUOKA, MASAOMITSUYA, HIROAKI
Owner YAMASA SHOYU CO LTD
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